Most forms of reversible contraception are practiced by the female member of an animal pair, whether the animal be human or not. With humans, physical (diaphragm and IUD) and chemicl ("the Pill", vaginal creams, foams, ointments, etc.) methods are available. At present there are only two acceptable methods for the human male. These are the condom and bilateral vasectomy. With the condom the failure rate is high, resulting in unwanted pregnancies. Vasectomies for practical purposes must be considered irreversible. Therefore, a method of male human contraception which is both reversible and reliable is highly desirable.
With regards to the non-human mammals a male contraceptive is also highly desirable. For non-domestic commercial animals such as horses, cattle, sheep, etc., the present situation is to separate male and female animals so the female may be selectively, artificially inseminated. It would, of course, be simpler to permit the animals to cohabitate under circumstances where the female cannot become pregnant. Domestic animals normally cohabitate because it is virtually impossible to separate male and female cats and dogs in a household. Many times it would be desirable to be able to prevent unwanted pregnancies of domestic animals under cohabitation circumstances. Additionally, with undesirable rodents a male contraceptive would be helpful to decrease fertility and thereby decrease or eliminate the number of undesirable rodents.
H. J. Ringold et al. in J. Am. Chem. Soc. 81, 427 (1959) disclose 17.beta.-hydroxy-2.alpha.-methyl-5.alpha.-androstances in general and in particular 17.beta.-hydroxy-2.alpha.-methyl-5.alpha.-androstan-3-one and 17.beta.-hydroxy-2.alpha.,17.alpha.-dimethyl-5.alpha.-androstan-3-one. U.S. Pat. No. 2,852,537 discloses 2.alpha.-alkyl-17.beta.-hydroxy-17.alpha.-vinyl and -17.alpha.-ethinylandrost-4-ene-3-one type compounds and their anti-androgenic properties. R. Youssefyeh in Tetrahedron Letters 2161 (1964) discloses some 2.alpha.-methyl and ethyl-17.beta.-hydroxy-5.alpha.-androstan-3-ones. U.S. Pat. No. 3,846,456 discloses 17.beta.-hydroxy-2.alpha.,7.alpha.-dimethylandrost-4-en-3-one and its use as an anti-fertility agent but without stating anti-fertility in the male or female.
17.beta.-Methoxy-5.alpha.-androstan-3-one is known, see U.S. Pat. No. 3,301,850, Example 14. 17.beta.-Cyclopentyloxy-5.alpha.-androstan-3-one is also known, see British Pat. No. 1,327,910.
The 2-spirocyclopropyl androstanes are known, see Chem. Ber. 1470 (1965) and French Pat. No. 1,384,279.
R. Weichert and E. Kaspar in Chem. Ber., 93, 1710 (1960) disclose 17.beta.-hydroxy and 17.beta.-acetoxy-1.alpha.,2.alpha.-methylene-5.alpha.-androstan-3-one. V. Mende et al. in Tetrahedron Letters 629 (1975) also disclose 17.beta.-acetoxy-1.alpha.,2.alpha.-methylene-5.alpha.-androstan-3-one. German Patent 1,961,906 discloses 17.beta.-hydroxy- and 17.beta.-acyloxy-7.alpha.-methyl-1.alpha.,2.alpha.-methyleneandrost-4-en-3 -one.
Both 17.beta.-hydroxy and 17.beta.-acetoxy-2-methyl-5.alpha.-androst-1-en-3-one are known, see J. Am. Chem. Soc. 82, 5494 (1960). The unsaturated compound 17.beta.-hydroxy-1-methyl-5.alpha.-androst-1-en-3-one is also known, see Arzneimittel Forschung 12, 218 (1962).
U.S. Pat. No. 3,415,816 discloses a process to prepare 17.beta.-hydroxy-5.alpha.-androstan-2-one and esters thereof. 17.beta.-Hydroxy-3.beta.-methyl-5.alpha.-androstan-2-one is disclosed in Steroids 27, 581 (1976).
P. D. Klimstra and R. E. Counsell in J. Med. Pharm. Chem. 5, 1216 (1962) disclose 2.alpha.-fluoro-17.beta.-hydroxy-5.alpha.-androstan-3-one. J. Edwards and H. J. Ringold in J. Am. Chem. Soc. 81, 5262 (1959) disclose 2.alpha.-fluoro-17.beta.-hydroxy-17.alpha.-methyl-5.alpha.-androstan-3-one . B. Ellis and V. Petrow in J. Chem. Soc. 3869 (1953) disclose a 2-chloro steroid, 2-chlorocholestan-3-one, see also J. Am. Chem. Soc. 75, 3500 (1953). U.S. Pat. No. 3,301,850 (Example 15) discloses 2.alpha.-bromo-17.beta.-methoxy-5.alpha.-androstan-3-one.
C. W. Shoppee in J. Chem. Soc. 1138 (1946) disclosed 3.alpha.- and 3.beta.-chloro-5.alpha.-androstan-17-ones. There is no disclosure of 3-chloro-17.beta.-hydroxy-5.alpha.-androstanes nor of their 17-ethers.
G. Ohta et al. in Chem. Pharm. Bull. 16, 1487 (1968) reported the synthesis of 17.beta.-hydroxy-2'-methyl-5.alpha.-androstano[2,3-d]oxazole as well as the 17-acetate. P. DeRuggieri et al. very comprehensively reviewed the heterocyclic steroids in Farmaco Ed. Sci. 20, 280 (1965); no mention was made of [2,3-d]oxazole steroids. 17.beta.-Methoxy-5.alpha.-androst-2-en[2,3-d]isoxazole is known, see U.S. Pat. No. 3,980,638.
U.S. Pat. No. 3,704,295 discloses 17.beta.-hydroxy-5.alpha.-androstano[3,2-c]pyrazole (Example 6b) as well as 17.beta.-hydroxyandrost-4-eno[3,2-c]pyrazole (Example 9b). The 17.alpha.-methyl analogs, 17.beta.-hydroxy-17.alpha.-methyl-5.alpha.-androstano[3,2-c]pyrazole and 17.beta.-hydroxy-17.alpha.-methylandrost-4-eno[3,2-c]pyrazole are disclosed in J. Am. Chem. Soc. 71, 1513 (1959). U.S. Pat. No. 3,704,295 claims various [3,2-c]pyrazoles of the androstane series which are substituted on the pyrazole ring though few examples are given. S. Hayashi and T. Komeno in Chem. Pharm. Bull. 17, 1319 (1969) disclose 5'-aryl-5.alpha.-androstano[3,2-c]pyrazoles. U.S. Pat. No. 3,539,556 discloses 2'-aryl-17.alpha.-ethynyl-17.beta.-hydroxyandrostan-4-eno[3,2-c]pyrazoles. Two examples, Examples 13 and 14 disclose tetrahydropyranyl ethers. These compounds were disclosed as useful anti-inflammatory agents.
U.S. Pat. No. 3,030,358 discloses a reductive process for the transformation of androst-4-eno[3,2-c]pyrazoles to the corresponding androstano[3,2-c]pyrazole.
J. A. Zderic et al. in Chem. Ind. 1625 (1960) disclose 17.beta.-hydroxy-17.alpha.-methyl-5.alpha.-androstano[3,2-b]thiazole.
H. J. Ringold et al. in J. Am. Chem. Soc. 81, 427 (1959), and U.S. Pat. No. 3,135,743 both disclose various 2-hydroxymethylene-17.beta.-hydroxyandrostanes with and without unsaturation at C.sub.4 and with various substituents at the 17.alpha.-position such as hydrogen, methyl, ethyl and vinyl. U.S. Pat. No. 3,980,638, Example 3, discloses 17.beta.-methoxy-2-hydroxymethylene-5.alpha.-androstan-3-one. The 2-hydroxymethylene steroids were useful as intermediates in the production of steroido[2,3-d]isoxazoles.
Genkichi Ohta et al. in Chem. Pharm. Bull. 16, 1487 (1968) reported synthesis of 17.beta.-hydroxy-5.alpha.-androstano-[2,3-d]imidazole the 2'-methyl, and the 2'-methyl-17-acetate derivatives.
U.S. Pat. Nos. 3,026,317 and 3,132,137 both disclose 17.beta.-hydroxy-5.alpha.-androstane and androst-4-ene[3,2-d]pyrimidines and 17-acrylates thereof.
U.S. Pat. No. 3,301,850 discloses 2.alpha.,3.alpha.-thioepoxides of 5.alpha.-androstanes. Example 8 discloses the 17-tetrahydropyranyl ether; Example 17 the 17-methyl ether; and Example 19 the 17-ethyl ether. The utility disclosed for these compounds is as hormonal agents as evidenced by their anabolic properties and possessing the particular advantage of exhibiting only minimal anti-fertility side effects. The 2.alpha.,3.alpha.-epithio-5.alpha.-androstane 17-ethers (XV) of the present invention are useful as male contraceptive agents. U.S. Pat. No. 3,169,136, in particular Example 1, discloses a process to prepare 2.alpha.,3.alpha.-epoxy-5.alpha.-androstanes. In U.S. Pat. No. 3,169,136 the 2.alpha.,3.alpha.-epoxy-5.alpha.-androstanes are used as intermediates to prepare 2.beta.-halo-5.alpha.-androstanes. U.S. Pat. No. 3,682,898 discloses 17.beta.-hydroxy-2.alpha.,3.alpha.-epoxy- and 2.alpha.,3.alpha.-epithio-7.alpha.-methyl-5.alpha.-androstanes and esters thereof.
The oximes of 3-keto steroids are well known. U.S. Pat. No. 3,686,237 and A. F. Hirsh et al. in J. Med. Chem. 20, 1546 (1977) describe O-aryloximes of 3-keto androstanes. The oximes and O-substituted oximes of the 3-keto steroid 17-ethers (I-IV and VI) of the present invention are novel.
The various steroids discussed above were generally 17.beta.-hydroxy or 17-acrylates thereof. With the thioepoxides the utility alleged was hormonal ". . . and possess the particular advantage of exhibiting only minimal . . . anti-fertility side-effects." The epithio 17-ethers (XV) of the present invention are just the opposite: they are useful as male contraceptive agents. With the pyrazoles, U.S. Pat. No. 3,539,556 claims 17.beta.-hydroxy and 17-acyloxy steroido[3,2-c]pyrazoles. However, Examples 13 and 14 disclose tetrahydropyranyl ethers. Those ethers are not within the scope of the present invention, the tetrahydropyranyl ether group is very labile and following absorption it is readily lost while the ether groups of the present invention are retained for a much greater length of time.
Surprisingly and unexpectedly the 17-ethers of the present invention are useful as reversible male contraceptives upon oral administration.